1. Field of the Invention
The present invention provides a new temperature and moisture stable crystalline dihydrate form of the cephalosporin antibiotic, cefepime dihydrochloride.
2. Background Art
The antibiotic cefepime is disclosed by Aburaki, et al., in U.S. Pat. No. 4,406,899, issued Sep. 27, 1983 and has the chemical name of 7-[.alpha.-(2-aminothiazol-4-yl)-.alpha.-(Z)-methoxyiminoacetamido]-3-[(1- methyl-1-pyrrolidinio)methyl]-3-cephem-4-carboxylate. The cefepime described therein is in the zwitterionic form which is unstable at room temperature and loses 30% or more of its activity on storage at elevated temperatures (e.g. 45.degree. C. and above) for even one week.
In U.S. Pat. No. 4,910,301, issued Mar. 20, 1990 to Kaplan, et al, there is described the preparation of a series of crystalline acid addition salts of cefepime. The sulfuric, di-nitric, monohydrochloric, dihydrochloric, and di- and sesquiorthophosphoric acid addition salts, or solvates thereof, are described and reported to have superior temperature stability compared to the zwitterionic form of the aforementioned Aburaki, et al. Furthermore, the preferred dihydrochloride salt of cefepime is reported to exist in a monohydrate or a dihydrate pseudopolymorphic form. Unfortunately, the dihydrochloride monohydrate salt of cefepime is readily converted to a dihydrate form in the presence of high humidity and the resulting dihydrochloride dihydrate salt of cefepime was found to lose one mole of water when dried in vacuo or over a desiccant. Surprisingly, the present inventors have now discovered a new distinct polymorphic crystalline dihydrochloride dihydrate of cefepime and this new dihydrate is both temperature and moisture stable.
In U.S. Pat. No. 4,994,451, issued Feb. 19, 1991 to Kaplan, et al, there is claimed physical admixtures of the crystalline cefepime acid addition salts claimed in Kaplan, et al, U.S. Pat. No. 4,910,301 with pharmaceutically acceptable non-toxic organic or inorganic bases.